The proposed study will conduct targeted formative research to identify key social-ecological factors influencing the uptake of newly implemented syringe exchange programs (SEPs) among people who inject drugs (PWID) in rural Appalachian Kentucky (KY). The recent initiation of SEPs in this rural, resource poor area provides a unique opportunity to examine social drivers impacting uptake of an evidence-based structural level HIV prevention intervention among a highly vulnerable and understudied population of PWID, and to develop complementary intervention strategies for enhancing SEP utilization. Serious health consequences associated with opioid injection are at crisis levels: KY has the highest rate of acute hepatitis C (HCV) in the nation, particularly among persons aged ?30 years residing in non-urban areas, with a risk factor of injection drug use. In addition, a recent analysis by the CDC identified 8 counties in Appalachian KY as among the nation's top 10 most vulnerable to the rapid dissemination of HIV and HCV among PWID. Despite well- documented rural-urban differences in drug use patterns and social characteristics, there is a critical gap in our knowledge of social drivers of SEP uptake and utilization among PWID in rural communities. The implementation of structural level HIV prevention programming has been virtually absent in rural locations, and the applicability of research findings from urban SEPs is largely unknown. Such data are urgently needed to inform the continued refinement of SEP policies and practices for vulnerable rural PWID and to develop complementary multi-level prevention strategies to enhance access and utilization of rurally located SEPs. Guided by Social Ecological Theory, the Specific Aims of this exploratory mixed methods study are to: 1) Examine the uptake of SEPs in three Appalachian county HDs (Clark, Knox and Pike), through structured interviews with 350 PWID (175 SEP utilizers and 175 non-utilizers) to identify and compare the key differences between utilizers and non-utilizers in social ecological domains, including intrapersonal (e.g., HIV /HCV knowledge, rural identity), interpersonal (e.g., kinship, peer norms, social isolation); institutional (e.g., justice system involvement, law enforcement activity); community (e.g., community stigma, geographic distance); and public policy factors (e.g., SEP policies and practices (privacy/anonymity, hours, locations, distribution model, secondary exchange)) that influence SEP uptake and utilization; and, 2) Identify priority intervention targets and develop strategies to enhance uptake of SEPs among rural PWID, by conducting in-depth qualitative interviews with a strategically selected sample of PWID from Aim 1, as well as key health departments directors and SEP staff, local substance treatment providers, law enforcement, and other community stakeholders, to assess multi-level barriers to SEP utilization, acceptability and feasibility of complementary intervention strategies, and to develop recommendations for intervention priorities and practice changes to improve SEP uptake.